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theses

Wound care is a substantial portion of the global market and treatment of chronic wounds cost the U.S. 25 million yearly on average. Bacterial biofilms are comprised of exopolymer encased bacterial cells and pose as a major health problem, as they are present in 78% of chronic, non-healing wounds. These biofilms frequently harbor multi-drug resistant microbial organisms (MRDOs) such as Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, which are difficult to eradicate with commercial antibiotics and greatly inhibit wound healing. Treatment is further complicated by poor blood circulation in the surrounding tissue, which hinders delivery of antibiotics to the infected region.
Our goal is to overcome the limitations of commercial antibiotics by developing a novel “GRAPLON Hydrogel” nanomedicine. The GRAPLON Hydrogel consists of unique graft polyelectrolyte surfactant (PS) nanocomplexes of cationic antimicrobial peptides (CAPs) which are known to minimize the development of microbial drug resistance. The PS-CAP nanoparticles (graft polyelectrolyte lipopeptide nanocomplexes or “GRAPLONs”) are incorporated into a biopolymeric hydrogel that will function as a topical wound dressing. We hypothesize that the surfactant properties of the graft polyelectrolyte can cause physical disruption of biofilms and simultaneously enhance transmembrane CAP delivery. In addition, the topical hydrogel can allow localized and controlled CAP delivery to the infected region, thereby reducing drug exposure and thus improving both efficacy and safety.
The physical properties of PS-CAP nanoparticles and GRAPLON hydrogels were characterized by measuring size, charge, surface tension, and viscosity. It was found that for specific graft density PS-CAPs, particle hydrodynamic sizes were <200 nanometers and were dependent on the solution they were dialyzed with. After complexing with CAPs Polymyxin B (PB) and experimental cyclic lipopeptides (CLPs), zeta potentials increased from negative to more positive, indicating self-assembling nanoparticle activity of the anionic polymer and cationic peptide through charge-charge interactions. Although critical micelle concentrations could not be determined, PS solutions did show presence of surface activity which was likely due to their graft density percentage. In hydrogel formulations, viscosities were demonstrated to be tunable based on addition of two different biocompatible thickening agents and shear thinning was observed due to the presence of CAPs and PS-CAPs. Controlled release studies demonstrated release kinetics in both aqueous and hydrogel formulations of PS-CAPs that closely fitted the Korsmeyer Peppas kinetic model. Lastly, antibacterial activity was retained in in-vitro and in-vivo studies conducted on selected gram-positive and gram-negative bacterial biofilms. The cumulative results demonstrate great potential for the GRAPLON system to be an effective means of targeting bacterial biofilms in chronic wounds and providing a treatment that overcomes the current obstacles in this area of study.

ETD_9807

M.S.

Includes bibliographical references

doi:10.7282/t3-yc1x-2b43

ETD graduate

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